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Peripheral arterial disease is a common condition in older adults involving poor arterial circulation in the legs leading to leg pain and debility. The body's own circulating blood vessel stem cells may help to improve circulation. This study will test whether treatment with the drug granulocyte macrophage colony stimulating factor (GM-CSF) will improve symptoms and signs of peripheral arterial disease over placebo after four weeks of therapy. As well this study will examine whether improvements in blood vessel function can be observed. Finally, we will measure blood vessel function and stem cell levels in order to determine whether they can help to predict whether patients wither peripheral arterial disease will suffer further cardiovascular complications.

Condition or disease

Intervention/treatment

Phase

Peripheral Arterial Disease

Drug: Granulocyte-Macrophage Stimulating Factor (GM-CSF)Drug: Placebo

Phase 2

Detailed Description:

Peripheral artery disease (PAD) affects more than 8 million Americans. Although exercise, smoking cessation, anti-platelet therapy, cilostazol, statins and revascularization are used to treat PAD, men and women with PAD have significantly greater functional impairment and fasterfunctional decline than those without PAD. Stem and progenitor cell (PC) therapy that promotes neoangiogenesis is an emerging treatment modality in PAD. Progenitor cells, particularly those of endothelial origin, are involved in vascular repair and regeneration. They originate primarily but not exclusively from the bone marrow, differentiate into endothelial and other vascular cells, and contribute to neovascularization during tissue repair by direct and paracrine mechanisms. Endogenous, pharmacologically-stimulated, and exogenous PCs contribute to re-endothelialization and neovascularization. Granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) stimulate mobilization of hematopoietic and other PCs from the bone marrow.In the murine hind limb ischemia model, GM-CSF administered by injection or by plasmid transfer augments circulating levels of PCs, increases capillary density, and promotes arteriogenesis.GM-CSF also augments neo-endothelialization of denuded arteries, promotes proliferation, differentiation and survival of hematopoietic cells, monocytes and macrophages.

Exercise Tolerance Test (ETT) was conducted using the Gardner protocol. Participants exercised on a treadmill, starting at 2.0 mph. The intensity of exercise (speed) was increased in grade of 2% every 2 minutes. Participants were asked to exercise until symptom limitation and the time measured in seconds from the ETT was used for data analysis.

Exercise Tolerance Test (ETT) was conducted using the Gardner protocol. Participants exercised on a treadmill, starting at 2.0 mph. The intensity of exercise (speed) was increased in grade of 2% every 2 minutes. Participants were asked to exercise until symptom limitation and the time measured in seconds from the ETT was used for data analysis.

Claudication is pain, tired or weak feeling that occurs in the legs, usually during activity such as walking. The COT was measured as the time to onset of the participant's typical claudication as the maximum distance the patient could walk on the treadmill.

Claudication is pain, tired or weak feeling that occurs in the legs, usually during activity such as walking. The COT was measured as the time to onset of the participant's typical claudication as the maximum distance the patient could walk on the treadmill.

The WIQ quantifies walking difficulty on a 100-point scale, in which 0 indicates extreme difficulty and 100 indicates no difficulty with stair climbing elements.

Change in Score on Physical Composite Score (PCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months [ Time Frame: Baseline, 3 months ]

The SF-36 is a standard quality of life instrument. The PCS represents the the physical burden on quality of life and is a summary of questions related to physical impact of a disease or condition (physical function, role physical, bodily pain, and general health). PCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.

Change in Score on Physical Composite Score (PCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months [ Time Frame: Baseline, 6 months ]

The SF-36 is a standard quality of life instrument. The PCS represents the the physical burden on quality of life and is a summary of questions related to physical impact of a disease or condition (physical function, role physical, bodily pain, and general health). PCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.

Change in Score on Mental Composite Score (MCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months [ Time Frame: Baseline, 3 months ]

The SF-36 is a standard quality of life instrument. The MCS represents the the mental burden on quality of life and is a summary of questions related to mental impact of a disease or condition (mental function, role emotional, vitality, and mental health). MCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.

Change in Score on Mental Composite Score (MCS) Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months [ Time Frame: Baseline, 6 months ]

The SF-36 is a standard quality of life instrument. The MCS represents the the mental burden on quality of life and is a summary of questions related to mental impact of a disease or condition (mental function, role emotional, vitality, and mental health). MCS is a summary measure derived from 8 scale score and the score ranges from 0-100; higher scores indicate better performance.

Change in Score on Physical Functioning Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 3 Months [ Time Frame: Baseline, 3 months ]

The SF-36 is a standard quality of life instrument. The physical functioning represents limitations in physical activities because of health problems. Physical functioning is a summary measure derived from 8 scale scores and the score ranges from 0-100; higher scores indicate better performance.

Change in Score on Physical Functioning Subscale of the Short Form 36 Health Survey (SF-36) From Baseline to 6 Months [ Time Frame: Baseline, 6 months ]

The SF-36 is a standard quality of life instrument. The physical functioning represents limitations in physical activities because of health problems. Physical functioning is a summary measure derived from 8 scale scores and the score ranges from 0-100; higher scores indicate better performance.

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Ages Eligible for Study:

21 Years to 80 Years (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

160 males or post-menopausal females between 21 and 80 years of age. Female subjects must be (a) post-menopausal, (b) surgically sterile or (c) use adequate birth control and have a negative pregnancy test within 3 days prior to administration of study drug and should not be breastfeeding.

Documented PAD (By Ankle-Brachial Indices or Angiographically)

Clinically stable (at least 2 months) history of intermittent claudication with no change in symptom severity in the 2 months prior to screening.

On stable statin therapy for previous 3 months.

Peak Walking Time (PWT) between 1 and 12 minutes on a standardized Gardner treadmill protocol.

A Doppler-derived ankle-brachial index (ABI) of < 0.85 in the symptomatic limb after 10 minutes of rest at screening. For subjects with an ABI of >1.3 (non-compressible arteries) a Toe-Brachial Index (TBI) of < 0.70 must be obtained for subject qualification, or if ABI is > 0.85 to 1.0 , and a reduction of 20% in ABI measured within 1 minute of treadmill testing.

On appropriate and stable medical therapy for atherosclerosis for at least 2 months.